The investigation of the bicyclo[3.1.0]hexane template as a platform for the construction of novel conformationally locked carbocyclic nucleosides continues to yield many interesting compounds. We use these modified nucleosides with the intent of: (1) determining the conformational preferences of enzymes involved in the biochemistry of nucleosides, nucleotides, and oligonucleotides;and (2) developing selected compounds as possible antitumor/antiviral drugs based on our understanding of their biochemical mechanism of action. These efforts have resulted in the discovery of N-methanocarbathymidine (N-MCT), a compound active against herpes viruses 1 and 2, as well as human herpesvirus 8 associated with Kaposi sarcoma. This year, we completed a semi-prep synthesis of N-MCT (65 g) via contract. The licensing company, N-Scientific, received part of this material and with NIAID scientists they have studied the oral activity of the drug against HSV-2 in infected mice. The successful results prompted the company to initiate ongoing studies in a HSV-2 guinea pig vaginal model. Future toxicological and pharmacological studies will follow. Animal toxicity studies with D-carba-T (carbocyclic thymidine), a successfully kinased nucleoside that functions as a kinetic delayed chain terminator in HIV-infected cells, have been approved. The novel mechanism of action of this agent was recently published in J. Med. Chem. The synthesis of oligonucleotides carrying novel nucleosides that are locked toward one specific ring puckering is a field of increasing interest. The substitution of North and South guanines built on a bicyclo[3.1.0]hexane templateat several sites of the thrombin revealed for the first time the separate contributions of the sugar conformation and the disposition of the nucleobase to the stability of the aptamer. These results have appeared recently in the Nucleic Acids Research. The combined syntheses and anti-HIV studies on North and South bicyclo[3.1.0]hexene nucleosides was achieved during this period. The results appeared in the journal ChemMedChem and the paper was selected for display in the inside cover of the journal.